| 1. |
- Agarwal, Prasoon, et al.
(författare)
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CGGBP1 mitigates cytosine methylation at repetitive DNA sequences
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.
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| 2. |
- Bekkouche, Bo M.B., et al.
(författare)
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Comparison of Transparency and Shrinkage During Clearing of Insect Brains Using Media With Tunable Refractive Index
- 2020
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Ingår i: Frontiers in Neuroanatomy. - : Frontiers Media SA. - 1662-5129. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Improvement of imaging quality has the potential to visualize previously unseen building blocks of the brain and is therefore one of the great challenges in neuroscience. Rapid development of new tissue clearing techniques in recent years have attempted to solve imaging compromises in thick brain samples, particularly for high resolution optical microscopy, where the clearing medium needs to match the high refractive index of the objective immersion medium. These problems are exacerbated in insect tissue, where numerous (initially air-filled) tracheal tubes branching throughout the brain increase the scattering of light. To date, surprisingly few studies have systematically quantified the benefits of such clearing methods using objective transparency and tissue shrinkage measurements. In this study we compare a traditional and widely used insect clearing medium, methyl salicylate combined with permanent mounting in Permount (“MS/P”) with several more recently applied clearing media that offer tunable refractive index (n): 2,2′-thiodiethanol (TDE), “SeeDB2” (in variants SeeDB2S and SeeDB2G matched to oil and glycerol immersion, n = 1.52 and 1.47, respectively) and Rapiclear (also with n = 1.52 and 1.47). We measured transparency and tissue shrinkage by comparing freshly dissected brains with cleared brains from dipteran flies, with or without addition of vacuum or ethanol pre-treatments (dehydration and rehydration) to evacuate air from the tracheal system. The results show that ethanol pre-treatment is very effective for improving transparency, regardless of the subsequent clearing medium, while vacuum treatment offers little measurable benefit. Ethanol pre-treated SeeDB2G and Rapiclear brains show much less shrinkage than using the traditional MS/P method. Furthermore, at lower refractive index, closer to that of glycerol immersion, these recently developed media offer outstanding transparency compared to TDE and MS/P. Rapiclear protocols were less laborious compared to SeeDB2, but both offer sufficient transparency and refractive index tunability to permit super-resolution imaging of local volumes in whole mount brains from large insects, and even light-sheet microscopy. Although long-term permanency of Rapiclear stored samples remains to be established, our samples still showed good preservation of fluorescence after storage for more than a year at room temperature.
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| 3. |
- Ciesla, Maciej, et al.
(författare)
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m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis
- 2023
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 83:7, s. 11-1179
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Tidskriftsartikel (refereegranskat)abstract
- SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDSs), which are clonal hematopoietic disorders with variable risk of leukemic transformation. Although tumorigenic SF3B1 mutations have been extensively characterized, the role of “non-mutated” wild-type SF3B1 in cancer remains largely unresolved. Here, we identify a conserved epitranscriptomic program that steers SF3B1 levels to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals dynamic regulation of SF3B1 protein abundance, which affects MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven 5′ UTR m6A demethylation fine-tunes SF3B1 translation directing splicing of central DNA repair and epigenetic regulators during transformation. This impacts genome stability and leukemia progression in vivo, supporting an integrative analysis in humans that SF3B1 molecular signatures may predict mutational variability and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.
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| 4. |
- Fritz, Björn, et al.
(författare)
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Angående det dokumentära
- 2007
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Ingår i: Fotografi i Fokus 2007. - 9789163303715 ; , s. 15-16
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Bokkapitel (populärvet., debatt m.m.)abstract
- Om gränserna för det dokumentära fotografiet och problemet med att anta att bilder dokumenterar en tänkt extern verklighet.
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| 5. |
- Fritz, Helena
(författare)
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Axl RTK and microRNAs in urogenital cancers
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on four projects focused on the Axl receptor tyrosine kinase (RTK) and microRNAs in clear cell renal cell carcinoma (ccRCC) and in prostate cancer (PCa). Paper I focuses on differentially expressed microRNAs in ccRCC. We used bioinformatics methods to identify candidate microRNAs in a publically available cohort of ccRCC, which were measured in a cohort of 198 RCC tumors. Importantly, we identified a 2-microRNA ratio, miR(21/10b), which is an independent prognostic factor in metastasis-free ccRCC patients. These microRNAs are both linked to chronic kidney disease, a risk factor for ccRCC, and could potentially be involved in the progression from kidney disease to renal cancer. In Paper II, our aim was to elucidate if members of the miR-34 family, which is a family of microRNA tumor suppressors, could regulate Axl in ccRCC, and also to determine miR-34a/b/c expression in ccRCC tumors, as reports have been conflicting. Axl has previously been shown to be a target of miR-34a in solid cancers, and high Axl expression correlates with worsened prognosis in RCC. We showed that both miR-34a and miR-34c are direct regulators of Axl in vitro, however miR-34a expression is increased in ccRCC and does not correlate with Axl mRNA or protein in ccRCC tumors, and has no correlation with survival in ccRCC. Paper III was aimed at elucidating whether any of the miR-34 family members could regulate Axl expression PCa, as both miR-34a and miR-34c are downregulated in PCa, and Axl expression is increased in PCa and correlates with disease severity. In addition, we sought to elucidate the role of decreased Axl expression in miR-34a/c-mediated tumor suppression. Although we could show direct regulation of Axl by miR-34a and miR-34c, our results did not support regulation of Axl as the main function in miR-34a/c tumor suppression in PCa. The main functional outcome of miR-34a/c-mediated loss of Axl seemed to be in reduced proliferation in response to Gas6. Finally, paper IV has the aim of investigating the role of Gas6/Axl signaling in Sunitinib treatment in ccRCC. Axl has been linked to resistance to targeted therapies in cancer. Sunitinib is an angiogenesis-inhibiting drug used in treatment of advanced ccRCC, however disease progression eventually occurs in many patients. We show that Sunitinib does not inhibit Axl activation by Gas6; instead Axl phosphorylation was enhanced in the presence of Gas6 and Sunitinib, both in ccRCC cells and in endothelial cells. Moreover, we observed activation of Akt pathway in Sunitinib-treated cells, which was enhanced by the addition of Gas6. In addition Sunitinib activated the epidermal and hepatocyte growth factor receptors, an effect that was augmented by Gas6. Interestingly, Gas6 stimulation was associated with secretion of Osteopontin, associated with tumor angiogenesis, an effect that was increased by Sunitinib.
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| 6. |
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| 7. |
- Fritz, Helena, et al.
(författare)
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The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.
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| 8. |
- Fritz, Helena, et al.
(författare)
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The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:10, s. 1758-1765
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. Experimental design: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n = 152) and 50 normal kidney samples. Results: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b),) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P = 0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P = 0.016; confidence interval (CI) 1.201-5.736). Conclusions: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance.
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| 9. |
- Gustafsson, Anna, et al.
(författare)
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Gas6-Axl signaling in presence of Sunitinib is enhanced, diversified and sustained in renal tumor cells, resulting in tumor-progressive advantages
- 2017
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 355:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Clear Cell Renal Cell Carcinoma (CCRCC) is a lethal cancer with bad prognosis due to development of chemoresistance and recurrence of more aggressive tumors. Investigation of Gas6-mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner. Gas6-induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl-dependent EGFR and METR activation and activation of classical MAPK pathways. Gas6+Sunitinib-adapted CCRCC cells present increased viability and decreased apoptosis and enhanced production of the multi-tumorigenic Osteopontin (OPN) and of one of its activator matrix metalloproteinase-7. Axl activity is necessary for CCRCC cell sphere formation and the ability of the cells to attach after non-adhesive growth. In addition, Gas6+Sunitinib-adapted CCRCC cells displayed enhanced migration and sphere formation, both mechanisms being Axl and OPN dependent. Altogether, this suggests that Sunitinib while targeting endothelial cells and tumor angiogenesis, simultaneously provides protumorigenic effects due to a constitutively, intensified and divergent Gas6-Axl system. Implications: Gas6-mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors. Therefore, combinatorial Axl-targeted therapy might be beneficial for CCRCC patients intended for Sunitinib treatment.
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| 10. |
- Tanski, George, et al.
(författare)
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The Permafrost Young Researchers Network (PYRN) is getting older : The past, present, and future of our evolving community
- 2019
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Ingår i: Polar Record. - 0032-2474 .- 1475-3057. ; 55:4, s. 216-219
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Tidskriftsartikel (refereegranskat)abstract
- A lasting legacy of the International Polar Year (IPY) 2007-2008 was the promotion of the Permafrost Young Researchers Network (PYRN), initially an IPY outreach and education activity by the International Permafrost Association (IPA). With the momentum of IPY, PYRN developed into a thriving network that still connects young permafrost scientists, engineers, and researchers from other disciplines. This research note summarises (1) PYRN's development since 2005 and the IPY's role, (2) the first 2015 PYRN census and survey results, and (3) PYRN's future plans to improve international and interdisciplinary exchange between young researchers. The review concludes that PYRN is an established network within the polar research community that has continually developed since 2005. PYRN's successful activities were largely fostered by IPY. With >200 of the 1200 registered members active and engaged, PYRN is capitalising on the availability of social media tools and rising to meet environmental challenges while maintaining its role as a successful network honouring the legacy of IPY.
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| 11. |
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